Examining the hormonal dynamics that characterize the menopausal transition by accurately assaying reproductive ligands is central to understanding the impact of menopause on women's health from midlife through old age. Fundamentally, the Endocrinology of the Menopause/CLASS Laboratory component will examine the dynamics and provide the endocrinologic scaffolding for all other projects in SWAN. We will characterize the hormonal changes associated with the menopausal transition and precisely relate these to their clinical manifestations, explore new areas of endocrine importance, and extend the study of hormonal characteristics from the early to late postmenopause. We will challenge the traditional concept of the menopausal transition as simply a loss of ovarian estradiol secretion to a more integrated and data driven model of a shift from an estrogen dominant to an androgen dominant balance of sex steroids modulated by a dynamic hepatic globulin system. Through SWAN I, II and III we have shown, both cross-sectionally and longitudinally: 1) sex hormone binding globulin (SHBG) to be most strongly associated with cardiovascular risk factors, metabolic syndrome, body composition, insulin, and glucose levels; 2) androgens to be strongly associated with cardiovascular risk factors, metabolic syndrome, body composition, insulin and glucose levels, and sexual function; 3) follicle stimulating hormone to be strongly associated with bone loss, vasomotor symptoms and timing of the final menstrual period; 4) a transient increase in adrenal androgen secretion coincides with the late perimenopausal drop in estradiol secretion; 5) only modest associations of estradiol with vasomotorsymptoms, metabolic and hemostatic factors but not bone loss. These findings provide endocrinological support for the evolution in thinking of the menopausal transition as an integrated shift from an estrogen dominant to an androgen dominant state with health risks associated with the magnitude of that shift. To characterize completely the natural history of the menopausal transition, we will pursue the following Specific Aims: 1) Add measures of circulating A and E1 to the annually measured T and E2 to provide a more complete estimate of total circulating estrogens and androgens. We shall calculate the equilibrium among these four steroids and the relationship of the equilibrium to SHBG, both cross-sectionally and longitudinally; 2) Measure the isoforms of SHBG and relate the relative proportions to sex steroid levels and ethnic differences, both cross-sectionally and longitudinally; and 3) Determine the degree to which the measured circulating adrenal androgens are associated with health outcomes in women traversing the menopause. We will continue serum sampling of previously measured hormones. RELEVANCE (See instructions): These studies will increase our understanding of the hormonal physiology of the entire menopausal transition and assist in the development of evidence-based paradigms for treating peri- and postmenopausal health concerns.